2. Academic Validation
  3. INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors

INX-315, a selective CDK2 inhibitor, induces cell cycle arrest and senescence in solid tumors

  • Cancer Discov. 2023 Dec 4. doi: 10.1158/2159-8290.CD-23-0954.
Catherine Dietrich 1,  Alec Trub 2,  Antonio Ahn 1,  Michael Taylor 3,  Krutika Ambani 1,  Keefe T Chan 4,  Kun-Hui Lu 5,  Christabella A Mahendra 1,  Catherine Blyth 1,  Rhiannon Coulson 3,  Susanne Ramm 5,  April C Watt 1,  Sunil Kumar Matsa 6,  John Bisi 2,  Jay Strum 7,  Patrick Roberts 7,  Shom Goel 8
Affiliations

Affiliations

  • 1 University of Melbourne, Australia.
  • 2 Incyclix Bio, Durham, NC, United States.
  • 3 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 4 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • 5 Peter MacCallum Cancer Centre, Melbourne, Australia.
  • 6 Ayurveda Molecular Modeling, India.
  • 7 Incyclix Bio, United States.
  • 8 University of Melbourne, Melbourne, VIC, Australia.
PMID: 38047585 DOI: 10.1158/2159-8290.CD-23-0954
Abstract

Cyclin-dependent kinase 2 (CDK2) is thought to play an important role in driving proliferation of certain cancers, including those harboring CCNE1 amplification and breast cancers that have acquired resistance to CDK4/6 inhibitors (CDK4/6i). The precise impact of pharmacological inhibition of CDK2 is not known due to the lack of selective CDK2 inhibitors. Here we describe INX-315, a novel and potent CDK2 Inhibitor with high selectivity over Other CDK family members. Using cell-based assays, patient-derived xenografts, and transgenic mouse models, we show that INX-315 (i) promotes retinoblastoma protein hypo-phosphorylation and therapy-induced senescence (TIS) in CCNE1-amplified tumors, leading to durable control of tumor growth; (ii) overcomes breast Cancer resistance to CDK4/6i, restoring cell cycle control whilst re-instating the chromatin architecture of CDK4/6i-induced TIS; and (iii) delays the onset of CDK4/6i resistance in breast Cancer by driving deeper suppression of E2F targets. Our results support the clinical development of selective CDK2 inhibitors.

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